Fentanyl, also known as N-phenyl-N-[1-(2-phenylethyl)-4-piperidinyl] propanamide, and other substituted N-(4-piperidinyl)-N-amides are known in the art as potent analgesics and anesthetics (see, for example, U.S. Pat. Nos. 3,141,823; 3,164,600; 3,998,834; 4,167,574; 4,196,210 and 4,584,303). Such compounds tend to exhibit muscle rigidity in virtually all muscle groups especially chest and abdominal muscles which can interfere with positive pressure ventilation. (See, "Postoperative Rigidity Following Sufentanil Administration", Marc Goldberg, M.D. et al., Anesthesiology, Vol. 63 No. 2 August, 1985, pp. 199-200; and "Physiology of Alfentanil-Induced Rigidity", James L. Benthuysen, M.D. et al., Anesthesiology, Vol. 64, 1986, pp. 440-446 and publications cited therein).
Alpha-2 adrenergic agonists are known to decrease the stimulation-induced release of norepinephrine from central and peripheral adrenergic neurons leading to a decrease of sympathetic outflow (e.g., "Inhibitory Effects of Clondine on Responses to Sympathetic Nerve Stimulation in the Pithed Rat", J. D. Doxey et al., Br.J.Pharmacol, 61,559 (1977); "Effects of Clonidine on Central Sympathetic Tone, H. Klupp et al., Eur.J.Pharmacol. 10, 225 (1970); and "Centrally Mediated Decrease in Sympathetic Tone Induced by 2(2,6-dichlorophenylamino)-2 imidazoline", H. Schmitt et al., Eur.J.Pharmacol. 1, 147 (1967)). Such compounds are also known to have vasopressor and antihypertensive activity and include clonidine and derivatives thereof (U.S. Pat. Nos. 3,202,660 and 3,454,701) guanfacine and derivatives thereof (U.S. Pat. No. 3,632,645), guanabenz (U.K. Patent No. 1,019,120) and alpha-methyl DOPA (U.S. Pat. No. 3,230,143).
Applicants have discovered that the administration of an injectable pharmaceutical composition containing the above-mentioned substituted N-(4-piperidinyl)-N-amides (e.g., fentanyl) and alpha-2-adrenergic agonists (e.g., clonidine) provides the same desirable anesthetic effect but substantially eliminates the muscle rigidity associated with the administration of compositions containing the substituted amides alone. Furthermore, the present pharmaceutical composition reduces the amount of anesthetic needed to induce anesthesia by as much as seven times and also reduces the amount of inhalation anesthetic often used to maintain anesthesia. Still further the present composition stablizes cardiovascular parameters during anesthesia.
It is therefore an object of the present invention to provide an injectable pharmaceutical anesthetic composition that substantially eliminates the side-effect of muscle rigidity.
It is another object of the invention to provide an injectable pharmaceutical composition wherein a reduced amount of substituted N-(4-piperidinyl)N-amide is needed to achieve the onset of anesthesia.
It is another object of the invention to provide an injectable pharmaceutical composition which reduces the amount of inhalation anesthetic used to maintain anesthesia.
It is another object of the invention to provide an injectable pharmaceutical anesthetic composition which maintains stabilized cardiovascular parameters.
It is another object of the invention to provide a method of anesthetizing warm blooded animals without the side effect of muscle rigidity.